The candidate is a junior researcher with considerable experience in studies of nonalcoholic fatty liver disease (NAFLD), metabolic syndrome and autophagy. However, in order for the applicant to transition into a fully independent investigator, an additional supervised training period is imperative. Dr. Mark J. Czaja has extensive research experience in the study of liver physiology, NAFLD and autophagy, will serve as an ideal mentor for this additional training. The research project will be carried out in the Marion Bessin Liver Research Center at the Albert Einstein College of Medicine which offers a scientifically motivating and inspiring environment and has a well-established liver research facility ideally suited to study altered cellular metabolism and physiology. The proposed five year career development plan is focused on: i) conferring upon the candidate a strong background in liver research, ii) improving his research skills and fundamentals as well as the learning of new experimental approaches, iii) facilitating productive collaborations with established researchers and iv) developing his teaching, training, and group leadership skills. The main goal of the current research project is to understand the mechanisms by which macroautophagy functions as a critical regulator of cellular lipid content through organ specific effects which lead to manifestations of the metabolic syndrome. We propose to test the hypothesis with studies in hepatocyte, adipocyte and a hypothalamic cells and autophagy knockout mouse models to delineate the function of autophagy in three interrelated organs that regulate whole body energy content and hepatic lipid accumulation. The studies are divided into three specific aims. First, we will determine whether macroautophagy regulates the development of steatohepatitis and hepatic insulin resistance. Second, we will establish that autophagy regulates adipose tissue mass and lipid content through effects on adipocyte differentiation. Third, we will demonstrate that autophagy regulates hypothalamic lipid metabolism in response to circulating nutrients, which then modulates orexigenic peptide secretion and food intake. The ultimate goal of these investigations is to better understand basic cellular mechanisms in three interrelated organs that regulate lipid metabolism and lipid accumulation in order to design new strategies for the prevention and treatment of human NAFLD.